A prodrug is a compound formed by chemical modification of a biologically active compound which will liberate the active compound in vivo by enzymatic or hydrolytic cleavage. The primary purpose of employing a prodrug for oral administration is to increase intestinal absorption or site specific absorption or to reduce local side effects, such as gastrointestinal irritation. Prodrugs may also be used to increase transdermal absorption, by enhancing permeation through topical membranes.
On this basis, prodrugs are not generally classified as sustained release dosage forms. However, the ability to bioreversibly modify the physicochemical properties of a drug allows better intestinal transport properties and hence can influence the drug blood levels versus time profile of the pharmaceutical compound. Thus, prodrugs can be used to increase the strategies for sustained release and, in a limited sense, can be sustaining in their own right.
U.S. Pat. No. 5,176,907 to Leong et al. discloses biocompatible and biodegradable poly(phosphoester-urethanes). The patent describes therapeutic agent delivery vehicles which include polymers which are biodegradable because of the hydrolyzable phosphoester or P--(O)--O--C bond. A particular aspect of the Leong patent is a therapeutic agent that can be .Introduced into the poly-phosphoester urethane by covalently binding a radical of this therapeutic agent to the phosphorous atom of the polymer. The patent describes attaching 5-fluorouracil to polyurethane. The patent discloses that drugs with carboxyl groups can be coupled to the phosphorous atom via an ester bond which is hydrolyzable.
U.S. Pat. No. 5,194,581 to Leong et al. discloses biodegradable polyphosphoesters. A therapeutic agent is pendently bound to a poly(phosphoester) polymeric matrix. When the therapeutic agent is pendently attached, it is chemically linked through, for example, ionic or covalent bonding. The drug is released when the polymeric agent biodegrades. A combination of one or more therapeutic agents can be incorporated into the composition of the invention. The patent discloses therapeutic agents containing two hydroxyl groups that can be directly incorporated into the backbone of the polymers. Other therapeutic agents can be derivatized for incorporation into the backbone. For instance, a drug with two amino groups can be reacted with the carboxyl group of a hydroxyl carboxylic acid. The hydroxyl groups can then be used to form the poly(phosphoester). A sustained delivery is effected by the hydrolysis of the polymeric prodrug. Although Leong discloses that two therapeutic agents may be bound to a polymer matrix via covalent bonding, he does not disclose or suggest that two therapeutic agents can be linked to one another by covalent bonding as a prodrug as in the present invention.
U.S. Pat. No. 5,104,877 to Boger discloses a psoriasis treatment. Boger describes a carboxy-protecting group used as a prodrug where the carboxy-protecting group can be readily cleaved in vivo. These carboxy protecting groups are indicated to be used in the protection of carboxyl groups in penicillin and cephalosporin.
U.S. Pat. No. 4,489,065 to Walton et al., discloses chondroitin drug complexes. The '065 patent describes that the rate of drug release can be controlled in a variety of ways, such as by encapsulation in a material which dissolves slowly in the body fluids, by entrapment in a bolus or matrix from which the drug diffuses slowly, or by conversion into a so called "prodrug", in which the drug is bound with another substance turning it into a substantially inactive compound or complex. The drug is gradually released by physiological action when injected into the tissues of the patient. The '065 patent discloses chondroitin or chondroitin sulphate covalently or ionically bonded to a drug substance of the group consisting of chloramphenicol, methotrexate, adriamycin, vinblastine, vincristine, vindesine, 6-mercaptopurine, 5-fluorouracil, penicillin antibiotics, cephalosporin antibiotics, and oxacephalosporin antibiotics, to form a prodrug. The patent states that the prodrug provides controlled release of the drug in a physiological environment. The patent discloses that a variety of functional groups are available in chondroitan for covalently bonding (particularly carboxyl, COOH, and hydroxyl, OH) and for ionic bonding (sulfate --OSO.sub.3 --, and carboxylate, --COO--) with drugs. Covalent bonding can be by way of ester links, --COOY, or amide links, --CONHY--. When chondroitin and the drug substance contain a hydroxyl and an amino group, the reaction can proceed through the formation of a carbamate bond via activation of the hydroxyl to a chloroformate moiety with subsequent linking to the amine function. The rate of release of the drug from the chondroitin or from the linking substance is dependent on the type of bonds chosen for linkage.
U.S. Pat. No. 5,130,126 to Koyama et al. discloses a polymer-drug conjugate and a method of producing it. Polymers which may be used have an alkyleneoxy group as a repeating unit such as polyoxyalkylene glycol as well as polymers obtained by substituting the terminal groups of the polymers with an acyl, amino or allyl group. Polymers are combined with drugs using covalent bonding, ionic bonding, coordinate bonding, and shiff base formation.
U.S. Pat. No. 5,057,301 to Wilbur et al. discloses modified cellular substrates used as linkers for increased cell retention of diagnostic and therapeutic agents. The invention of Wilbur et al. comprises a ligand-linker conjugate wherein the linker is a chemically modified cellular substrate having a protein conjugation group attached thereto. The protein conjugation group attached to the modified substrate linker is a functional group which will react with the group on the targeting protein and form a bond between the linker and the protein. Suitable protein conjugation groups include active esters (including carboxylic esters, imide esters, succinimidyl esters, phenolic esters, and imidate esters), primary or secondary amines, hydrazides, hydrazines, carboxylate, isothiocyanates, isocyanates, and Michael-type acceptor groups such as maleimides, thiols, anhydrides and alkyl halides.
U.S. Pat. No. 5,171,566 to Mizushima et al. discloses a flurbiprofen derivative ophthalmic preparation. The derivative is an ester of flurbiprofen. U.S. Pat. No. 4,933,324 to Shashoua is directed to a fatty acid-neuroactive drug conjugate used as a prodrug and involves the formation of a prodrug from a fatty acid carrier and a neuroactive drug. The bond between the fatty acid and the drug may be an amide or an ester bond. U.S. Pat. No. 4,975,278 to Senter et al. discloses antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells.
U.S. Pat. No. 4,267,326 to Ozaki et al. discloses uracil derivatives. The uracil derivatives are prepared by reacting 5-fluorouracil with an .alpha.-haloalkyl carboxylate or an aldehyde diacylate.
U.S. Pat. No. 4,897,260 to Ross et al. discloses glucocorticoid carboxylic acid esters which include triamcinolone acetonide 21-oic methylester for the treatment of xeroderma pigmentosum.
U.S. Pat. No. 4,910,192 to Avery et al. discloses topically active steroidal anti-inflammatory agents. The agents are 12-.beta. substituted glucocorticoids wherein the 12 substituent is a hydroxyl group or a lipophilic group attached to a 12-.beta.-hydroxyl group. The lipophilic group may be selected from an alkyl or aryl substituted ester, an ester, a carbamate and a carbonate groups. The 12th substituent can be a lower carboxylic acid ester of a 12-.beta.-hydroxy group.
U.S. Pat. No. 5,177,064 to Bodor discloses targeted drug delivery via phosphonate derivatives. U.S. Pat. No. 5,112,835 to Miyasaka et al. discloses 6-substituted acyclopyrimidine nucleoside derivatives for use as antiviral agents. Chemical Abstracts, Volume 117(8), abstract no. 76315(m) discloses the stereoselective enzymatic hydrolysis of various ester prodrugs of ibuprofen and flurbiprofen.
Chemical Abstracts, Volume 116(18), abstract no. 181046(b) describes the preparation of prodrugs of flurbiprofen, its 1,2-ethanediol ester and 1,4-butanediol ester. The prodrugs showed high stability in simulated gastric fluid, simulated intestinal fluid and simulated pancreatic fluid. The drugs showed less toxicity and increased anti-inflammatory and analgesic effects.
None of the above patents disclose or suggest prodrug conjugates of two or more of the same or different drugs linked to one another. Nor do they disclose codrug conjugates which are linked by reversible covalent bonds, such as ester, carbamate and carbonate bonds, so that at the desired site in the body they are cleaved to regenerate the active forms of each of the drugs.
Patient compliance in consumption of pharmaceutical compositions as part of a therapeutic regimen is critical for patient recovery and treatment. This is especially critical in elderly patients who may have poor memory and who exhibit poor patient compliance with a therapeutic regimen of doses of pharmaceutical compositions. Other high risk compliance groups include drug addicts, alcoholics and those requiring long term therapy, for example tuberculosis patients.
Furthermore, known erodible, implantable pharmaceutical substances such as polylactic acid and polyurethane compounds are formulated such that it is difficult to achieve high drug loading and hence difficult to deliver large doses of drug from the substrate. Such drug substances have low solubility.
There is a need in the pharmaceutical arts for pharmaceutical compounds which deliver two or more drugs at a single time in a single dose, which exhibit controlled drug delivery. In one embodiment, the pharmaceutical compounds of the present invention are delivered in a totally erodible drug delivery device capable of delivering two or more synergistic drugs over a prolonged period. The codrug compounds of the present invention have the advantage that linking the two drug compounds decreases the solubility of each through the carbamate, carbonate and ester bonds linking the compounds. The codrug compounds of the invention have a high degree of chemical or enzymatic lability at physiological pH 7.4.